Methods

RCT, 2‐arm, parallel design

Participants

Total number of randomized participants: 80

Inclusion criteria

1. Critically ill, mechanically ventilated people in the ICU

Exclusion criteria

1. Not reported in abstract

Baseline characteristics

No details reported in abstract

Country: not reported (published in Croatian journal)

Setting: ICU

Interventions

EN group

n = 40

Details: nutritional requirements based on Harris‐Benedict equation. Formula consisted of fat, carbohydrate, and protein. Identical to PN group

PN group

n = 40

Details: nutritional requirements based on Harris‐Benedict equation. Formula consisted of fat, carbohydrate, and protein. Identical to EN group

Outcomes

1. Serum glucose levels

2. Nosocomial bloodstream infections

3. Septic morbidity

4. LOS in ICU and hospital

5. Duration of mechanical ventilation

6. Mortality

Notes

Funding/declarations of interest: not reported

Study dates: not reported

We were unable to source the full‐text of this study, and did not have the study authors' contact details to attempt contact.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details. Abstract only

Allocation concealment (selection bias)

Unclear risk

No details. Abstract only

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details. Abstract only. We assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details. Abstract only

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Abstract only. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No details. Abstract only. Outcome data were well reported and we assumed there were no losses

Selective reporting (reporting bias)

Unclear risk

No details. Abstract only

Baseline characteristics

Unclear risk

Study authors described participants as matched on SAPS II, age, and primary diagnoses. No baseline characteristics tables or additional detail available

Other bias

Unclear risk

Study authors described nutritional formula of both groups as identical. Insufficient detail in abstract to make judgement on other sources of bias

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 20

Inclusion criteria

1. > 18 years of age, recent ICU admission (< 24 hours), having SIRS, APACHE II > 10, expected not to feed via oral route for ≥ 5 days

Exclusion criteria

1. People with high probability of death in next 7 days of admission

2. Pregnant or lactating

3. Having contraindications to EN

Primary diagnoses

1. SIRS

Baseline characteristics

EN group

1. Age, mean (SD): 58.4 (± 5.07) years

2. Gender: not reported

3. APACHE II, median: 17.0

4. SOFA, median: 9.0

EN + PN group

1. Age, mean (SD): 54.9 (± 5.16) years

2. Gender: not reported

3. APACHE II, median: 18.5

4. SOFA, median: 7.0

Country: Iran

Setting: ICU

Interventions

EN group

n = 10; 0 losses

Details: nasogastric tube feeding for 7 days. Feeding formula was Fresubin Original (Fresenius Kabi, Germany) given in solution as 1 kcal/mL. Average 70 kg participant initially received 50 mL every 3 hours, increased with 50 mL increments to maximum 300 mL every 3 hours at rate of 100 mL/h. GRV threshold at 300 mL with delay of feeding for 3 hours if threshold was reached. Glycaemic management not reported.

EN + PN group

n = 10; loss of 1 participant on day 3 (move to different hospital); number analysed assumed to be 9.

Details: EN as above. PN consisted of 500 mL of 10% AA solutions (B Braun, Germany), 500 mL of 50% dextrose, infused over 24 hours. Equivalent management of GRV. Duration of feeding for 7 days

Outcomes

1. Mortality (within 7 days)

2. Analysis of inflammatory markers

3. Length of ICU and hospital stay

Notes

Funding/declarations of interest: partly supported by grant from Tehran University of Medical Sciences

Study dates: November 2007 to May 2009

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 participant moved to another hospital after 3 days, not clear whether data for this participant were sourced but small loss unlikely to influence outcome data

Selective reporting (reporting bias)

Unclear risk

No protocol or clinical trials registration reported. Therefore, not feasible to make judgement on selective outcome reporting bias

Baseline characteristics

Low risk

Appeared to be equivalent between groups

Other bias

Low risk

Glycaemic management equivalent for each group. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 46

Inclusion criteria

1. 18 to 60 years of age

2. 80% to 130% of desirable bodyweight

3. Significant injuries to ≥ 2 body systems

Exclusion criteria

1. History of hepatic or renal failure

Primary diagnoses

1. People with trauma injuries to include: head injury, spinal fracture, severe facial fractures, severe thoracic injury, major intra‐abdominal injury, pelvic fracture, long bone fractures, or other major soft‐tissue injury

Baseline characteristics

EN group

1. Age, mean (SD): 30 (± 9) years

2. Gender M/F: 15/8

3. APACHE II: not reported

PN group

1. Age, mean (SD): 29 (± 10) years

2. Gender M/F: 16/7

3. APACHE II: not reported

Country: USA

Setting: medical centre

Interventions

EN group

n = 23; 0 losses; 4 participants required conversion to PN; assume ITT analysis

Details: jejunostomy tube placement. Feeding started on first postoperative day. Feeding assumed to be for duration of study period (14 days). Target rate changed during study as participants in both groups appeared to have insufficient nitrogen balance; Phase 1: target rate calculated as Harris‐Benedict BEE x 1.68, Phase 2: target rate calculated as Harris‐Benedict BEE x 2.0 plus an additional 20%. Formula consisted of polymeric feeding solution (5 participants received Isocal HCN: 15% protein calories, 45% carbohydrate calories, 49% lipid calories. 18 participants received Traumacal: 22% protein calories, 40% carbohydrate calories, 48% lipid calories) (Mead Johnson Nutritional Division, Evansville, IN, USA). Participants given insulin to manage blood glucose levels. Metabolic or gastrointestinal intolerances were treated by physician as required.

Caloric intake received, mean: Phase 1: 2088 calories; Phase 2: 2678 calories

PN group

n = 23; 0 losses

Details: subclavian line placement. Feeding started on first postoperative day, assumed duration of study period (14 days). Phase 1: target rate calculated as Harris‐Benedict BEE x 1.68, Phase 2: target rate calculated as Harris‐Benedict BEE x 2.0. Formula consisted of 25% dextrose, 4.25% crystalline AAs (Travasol: Baxter Healthcare Corporation, Deerfield, IL, USA). Additional caloric prescriptions of 500 mL of 10% lipid, twice weekly, were optional. 50 mL per hour for first 24 hours, then advanced as tolerated at physician's discretion.

Caloric intake received, mean: Phase I: 2572 calories; Phase 2: 2876

Outcomes

1. Length of hospital stay

2. Length of ICU stay

3. Length of time on the surgical service

4. Number of ventilator days

5. Number and type of operations

6. Total number of days receiving EN or PN

7. First day of oral intake

8. Weight at time nutritional support was discontinued

9. Medical complications (wound infection, pneumonia, intra‐abdominal infection, persistent fever, gastrointestinal bleeding, hepatic failure, acute renal failure, pancreatitis)

10. Complications (bloating, cramps, nausea; diarrhoea (diagnosed by 3 to 6 loose or liquid stools per day, or > 6 loose stools for severe diarrhoea)

11. Catheter sepsis (not clearly reported)

12. Mortality

13. Costs of nutritional support

Notes

Funding/declarations of interest: supported, in part, by a grant from Mead Johnson Nutritional Division, Evansville, IN, USA

Study dates: January 1982 to June 1984

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomized by surgical team in operating theatre. No additional information provided

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed that investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No evidence of blinding. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trial registration or prospectively written protocol not reported. Not feasible to judge selective outcome reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Unclear risk

Changes to feeding protocol during study, but target rates were comparable between groups. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 71

Inclusion criteria

1. Needed invasive mechanical ventilation in the ICU

Exclusion criteria

1. Informed consent could not be obtained

2. Participant received > 48 hours of mechanical ventilation in another unit

3. Participant required < 72 hours of mechanical ventilation in the ICU or died within the first 72 hours

4. Randomized route of nutrition support was medically contraindicated

5. Nutrition support could not be started because of severe metabolic/haemodynamic instability during the first 48 hours of ventilation, or the participant was already receiving nutrition support at the time of intubation

Primary diagnoses

1. Acute respiratory failure

2. Acute neurological pathology

3. Severe metabolic/renal disease

4. Intoxication

5. Postoperative complications, or other diagnoses

Baseline characteristics

EN group

1. Age, mean (SD): 57.77 (± 19.88) years

2. Gender M/F: 15/15

3. APACHE II, mean (SD): 20.03 (± 7.43)

PN group

1. Age, mean (SD): 57.95 (± 18.00) years

2. Gender M/F: 23/18

3. APACHE II, mean: 22.66 (± 7.47)

Country: Turkey

Setting: university hospital, medical ICU

Interventions

EN group

n = 30; 0 losses; ITT analysis

Details: preference for postpyloric tube placement, otherwise gastric feeding, feeding initiated within 48 hours, at target rate of 25 to 30 kcal/kg/day using ideal bodyweight, formula with proteins, carbohydrates, and lipids. 20 mL/hour of standard solution, increased every 4 to 6 hours by 20 mL/hour if GRV < 150 mL. Continuous infusion of insulin as needed with target level of 100‐140 mg/kL.

Caloric intake received, reported as mean (SD) percentage of target calories given: 46.48 (± 19.34)

PN group

n = 41; 0 losses; deviations from protocol for 3 participants who were changed to EN feeding due to clinical needs; ITT analysis

Details: preference for central or venous route, according to participant condition and contraindications to central venous line insertion, otherwise peripheral route. Target rate of delivery and glycaemic management same as EN group. Feeding started at full dose, unless participant at risk of refeeding syndrome, or severely malnourished and already had electrolyte disturbance.

Caloric intake received, reported as mean (SD) percentage of target calories given: percentage of target calories given 66.78 (SD ± 18.85)

Outcomes

1. Mortality (in hospital and ICU)

2. Pneumonia (diagnosed according to ACCP consensus statement)

3. Sepsis

4. Catheter infections

5. Diarrhoea (diagnosed by an increase in stool amount > 1 L and frequency > 3/day with loss of consistency)

6. Vomiting

7. Hypervolaemia

8. Severe shock

9. Length of ICU stay

10. Length of mechanical ventilation

11. Achievement of feeding goals

12. Interruption of feeding

Notes

Funding/declarations of interest: no details

Study dates: February 2004 to January 2006

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quasi‐randomized method of sequence generation.

Quote: "Patients were randomized to receive either EN or PN according to the last digit of their assigned hospital record number: odd numbers received PN, and even numbers received EN"

Allocation concealment (selection bias)

Low risk

Adequate concealment despite inadequate sequence generation. Hospital record numbers were assigned by staff independent of the ICU team

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence assessment of outcomes for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses but deviations from protocol in 3 participants in PN group. ITT analysis used

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not possible to make assessment of selective outcome reporting bias

Baseline characteristics

Unclear risk

More sepsis and acute pathology in PN group; not reported as statistically significant. Unclear if these differences could influence outcome data. Also, we noted that number of participants in each group was not equivalent (41 in PN group; 30 in EN group) and this was not explained

Other bias

Low risk

Glycaemic controls equivalent between groups. Nutritional goals appeared to be equivalent. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 120

Inclusion criteria

1. > 18 years of age, admitted to the ICU for > 2 days, expected to stay alive > 2 days. Expected to eat < 20 kcal/kg/day for > 2 days, and EN to be progressively administered for > 2 days

Exclusion criteria

1. Postelective surgery patients

2. People with contraindication to enteral or parenteral feeding

3. History of allergy to vitamins

Primary diagnoses

1. Multiple trauma

2. Respiratory failure

3. Stroke

4. Sepsis

5. Coronary artery disease

6. Poisoning

7. Renal failure

8. Gastrointestinal bleeding

Baseline characteristics

EN group

1. Age, mean (SD): 55 (± 18) years

2. Gender, M/F: 42/18

3. SAPS II, mean (SD): 41 (± 13)

EN + PN group

1. Age, mean (SD): 53 (± 18) years

2. Gender, M/F: 40/20

3. SAPS II, mean (SD): 43 (± 14)

Country: France

Setting: 2 ICUs (medical and surgical) at same hospital

Interventions

EN group

n = 60; 7 losses; ITT analysis

Details: feeding for 4 to 7 days with target rate of delivery 25 kcal/kg bodyweight/day = 100 kcal carbohydrates‐fat per gram of nitrogen. Typical 70 kg person received 100 mL initially, with an increased amount in 50 mL steps to a maximum of 350 mL every 4 hours. Feeding solution consisted of protein (20%), polyunsaturated fats (30%), carbohydrates (50%), non‐soluble fibres, sodium chloride, potassium chloride, hydrosoluble and liposoluble vitamins. All participants in the EN group also received placebo PN formula, consisting of: sodium chloride, Intravit, Soluvit (Pharmacia and Upjohn, St Quentin‐Yvelines, France). GRV measured before each feed; delayed feeding if > 300 mL and cisapride added. Glucose level checked every 4 hours and maintained around 1.6 to 2 g/L with insulin using a sliding scale

Caloric intake received, mean (SD): EN: 9.9 (± 3.9) kcal/kg/day; PN: 1.4 (± 0.3) kcal/kg/day

EN + PN group

n = 60; 6 losses; ITT analysis

Details: EN composition as above. PN feeding through central line access. Feeding solution consisted of EN: protein (20%), polyunsaturated fats (30%), carbohydrates (50%), non‐soluble fibres, sodium chloride, potassium chloride, hydrosoluble and liposoluble vitamins. PN: 3‐in‐1 solution of carbohydrates, lipids, and protein; Vitrimix (Fresenius Kabi); hydrosoluble vitamins; Soluvit (Pharmacia and Upjohn, St Quentin‐Yvelines, France).

Caloric intake received, mean (SD): EN: 11 (± 3.3) kcal/kg/day; PN: 13.9 (± 2.5) kcal/kg/day

Note: study authors reported that increases in EN were the same. PN increases were the same in theory, but not in actuality due to the lack of fat content in the EN group placebo feed

Outcomes

1. Mortality (reported at 90 days, ≤ 2 years)

2. Diarrhoea

3. Need for ventilator support

4. Circulatory, neurological, renal support

5. LOS (ICU and hospital)

6. Nosocomial infections

7. Number of days of ventilator support

Notes

Funding/declarations of interest: no reported details

Study dates: August 1996 to May 1997

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization carried out at central pharmacy but methods were not adequately described

Allocation concealment (selection bias)

Unclear risk

Use of sealed envelopes; no additional details

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Both participants and personnel were blind to the intervention.

Quote: "The bags were prepared under the label A or B. Neither the health care providers nor the patients were aware of their content. Both types of bags were opalescent by the adjunction of small amount of fat and vitamins."

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details. Statistician was blinded

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details; lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Some participants received sufficient nutrition by day 4, and some died by day 4 but no difference in these losses between groups and participants included in analysis as ITT

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not possible to make assessment on selective outcome reporting bias

Baseline characteristics

Low risk

Baseline characteristics were very similar between groups

Other bias

Low risk

Protocol for glycaemic management was the same for both groups. Other differences in nutritional protocol are due to study design (EN vs EN + PN). No other sources of bias identified

Methods

RCT, multi‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 36

Inclusion criteria

1. > 18 years of age, in high level care, in need of artificial ventilation and nutrition for ≥ 4 days

Exclusion criteria

1. Motor GCS < 4

2. Pure cerebral disease

3. Spinal trauma

4. Referral from ICUs in which participants stayed > 24 hours

Primary diagnoses

1. All had severe sepsis or septic shock; some participants had respiratory failure, or respiratory plus cardiovascular failure

Baseline characteristics

EN group

1. Age, mean (SD): 59.3 (± 17.6) years

2. Gender, M/F: 11/7

3. SAPS II, median (IQR): 41 (39 to 46)

4. SOFA, median (IQR): 7 (5 to 8)

PN group

1. Age, mean (SD): 59.0 (± 21.4) years

2. Gender, M/F: 10/11

3. SAPS II, median (IQR): 43 (35 to 51)

4. SOFA, median (IQR): 7 (6 to 8)

Country: Italy

Setting: 33 ICUs

Interventions

EN group

n = 17; note 1 participant wrongly randomized to non‐septic group (see Radrizzani 2006) and then analysed in this report; ITT analysis. 18 participants analysed.

Details: feeding initiated within 48 hours of ICU admission. Feeding started at 10 kcal/kg/day, rising to 25 to 28 kcal/kg/day by 4th day. Nutritional formula consisted of 55% carbohydrates, 25% fat, 21% protein, 1.3 kcal/mL, containing per 100 mL: L‐arginine 0.8 g, omega‐3 fatty acids 0.15 g, omega‐6 fatty acids 0.7 g, vitamin E 2.9 mg, β‐carotene 0.75 mg, zinc 2.2 mg, and selenium 7 μg (Perative Abbott).

Caloric intake received, mean (SD): 19.1 (± 7.6) kcal/kg/day over the first 6 days

PN group

n = 19; note 2 participants wrongly randomized to non‐septic group (see Radrizzani 2006) and then analysed in this report; ITT analysis. 21 participants analysed

Details: feeding protocol as for EN group. Nutritional formula consists of equivalent carbohydrates, fats, and proteins (59% carbohydrates, 23% fat, 18% protein) but does not appear to include additional vitamins/minerals

Caloric intake received, mean (SD): 25.9 (± 6.4) kcal/kg/day over the first 6 days

Outcomes

1. Mortality at 28 days and in the ICU

2. Length of ICU stay

Notes

Funding/declarations of interest: Abbott Italia

Study dates: November 1999 to April 2001

Note: study was described as an interim analysis. It is the same study as Radrizzani 2006 but data included were for a subgroup of participants with sepsis only.

Also, study authors considered the difference in caloric intake and differences in some baseline characteristics to be significant, and conducted an adjusted analysis after which they concluded that these factors were potentially confounding and subsequently ceased randomization into this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate sequence generation. Use of computer‐generated randomization code

Allocation concealment (selection bias)

Low risk

Adequate concealment.

Quote: "The randomisation code was generated by a computer programme at the co‐ordinating centre and was revealed to investigators by telephone at the moment of randomisation, once baseline data collection was completed."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

Study authors reported that outcome data analysts were not blinded; study authors did not report whether outcome assessors were blinded

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration or prospectively published protocol not reported. Not possible to make assessment on reporting bias

Baseline characteristics

Unclear risk

Study authors noted an imbalance in baseline characteristics (PN group had more women, more participants aged > 60 years, more participants with cardiovascular and respiratory failure) and completed adjusted analysis for these variables. We were unclear whether these differences may affect results for our outcomes

Other bias

Unclear risk

Participants in PN group were given more calories in first 3 days because of study design and study authors completed adjusted analysis for this variable. Participants in EN group given additional supplements of minerals/vitamins which are not included in PN formula. We were unclear whether these differences may affect results for our outcomes

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 59

Inclusion criteria

1. Adults, 18 to 60 years of age, with head injuries and a GCS ≤ 8, coma persisting > 24 hours

Exclusion criteria

1. Spinal cord injury

2. Pre‐existing metabolic disorders

3. Renal failure

4. Inflammatory bowel disease

5. Neurological prognosis of rapidly fatal injury

Primary diagnosis

1. Severe head injury

Baseline characteristics

EN group

1. Age, mean (SD): 26.2 (± 10.4) years

2. Gender, M/F: 21/7

3. APACHE II, mean (SD): 15.7 (± 3.5)

PN group

1. Age, mean (SD): 28.9 (± 10) years

2. Gender, M/F: 19/2

3. APACHE II, mean (SD): 14.9 (± 3.9)

Country: USA

Setting: level 1 trauma centre

Interventions

EN group

n = 36; 8 losses; 28 analysed. Per‐protocol analysis (except for mortality)

Details: jejunal tube placement, and gastrotomy tubes placed to drain stomach. Feeding started within 24 hours of randomization. Target rates calculated with Harris Benedict formula BEE + 50%. Initiated at 20% of target rate for 12 hours; 40% for 12 hours; 60% for 12 hours; 80% for 12 hours; then target rate. Formula was a Vivonex solution TEN (Norwich Eaton Pharmaceuticals, Inc, Norwich, NY, USA) consisting of 4.9 g/L glutamine, carbohydrates, fat, AAs, other minerals, and Travasol solution (Baxter Healthcare Corp, Deerfield, IL, USA) consisting of 3.21 g/L glutamine, carbohydrates, fat, AAs, other minerals. If extra protein was required then Travasol 10% was given to EN solution. At day 9 to 11, EN group converted from Vivonex TEN to Isotein HN via jejunal tube ("thus keeping both groups identical except for route")

PN group

n = 23; 2 losses; 21 analysed. Per‐protocol analysis (except for mortality)

Details: central venous catheter placement. Feeding continued for 5 days and then attempts to convert to gastric feeding by any routes at the discretion of the clinician. Target rates calculated with Harris Benedict formula BEE + 50%. Feeding initiated 40% target rate of 24 hours; 60% for 12 hours, 80% for 12 hours, then target rate. Formula was an Isotein HN solution (Sandoz Nutrition Corp: Minneapolis, MN, USA) consisting of carbohydrates, fat, AAs, and other minerals. If extra protein was required then Travasol 10% was given to PN solution

Outcomes

1. Infections

2. Nutrition‐related complications including hyperglycaemia (diagnosed by blood glucose level of > 180 mg/dL) and diarrhoea

3. Mortality

Notes

Funding/declarations of interest: financial support from Norwich Eaton Pharmaceuticals, NY, USA.

Study dates: July 1990 to December 1991

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate sequence generation. Computer‐generated random number tables

Allocation concealment (selection bias)

Low risk

Computer‐generated numbers and we assumed that allocation was concealed from investigators

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Some loss of participant data: 2 participants in EN group, 8 participants in PN group. Reasons for losses were explained and mortality data included these (death was one of reasons for loss)

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration or prospectively published protocol was not reported. Therefore, not feasible to make judgement on selective outcome reporting bias

Baseline characteristics

Low risk

Appeared comparable, although we noted a large difference in sample size between groups which was unexplained

Other bias

Unclear risk

Some possible differences in nutritional formula. Unclear if this was likely to influence data

Methods

RCT, multi‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 4640

Inclusion criteria

1. Adults admitted to participating ICUs, scored ≥ 3 on NRS, did not meet any of exclusion criteria

Exclusion criteria

1. < 18 years of age

2. Moribund or coded DNR

3. Enrolled in another trial

4. Had short‐bowel syndrome

5. Had home ventilation

6. In a diabetic coma

7. Referred with nutritional regimen

8. Pregnant or lactating

9. No central catheter

10. Taking oral nutrition

11. Readmitted to ICU

12. NRS score < 3

13. Other reason (not described by study authors)

14. Did not give consent

15. People with chronic malnourishment (BMI < 17 kg/m²) before admission to ICU

16. Referral from another ICU with an established regimen of EN or PN

Primary diagnoses

1. Cardiac surgery

2. Complicated abdominal or pelvic surgery

3. Transplantation

4. Trauma

5. Burns

6. Reconstructive surgery

7. Complicated pulmonary or oesophageal surgery

8. Respiratory disease

9. Complicated vascular surgery

10. Gastroenterological or hepatic disease

11. Complicated neurosurgery

12. Haematological or oncological disease

13. Neurological disease

14. Cardiovascular disease

15. Renal disease

16. Neurological presentation of medical disease

17. Metabolic disorder

18. Other (not described by study authors)

Baseline characteristics

EN group

1. Age, mean (SD): 64 (± 15) years

2. Gender, M/F: 1486/842

3. APACHE II, mean (SD): 23 (± 10)

EN + PN group

1. Age, mean (SD): 64 (± 14)

2. Gender, M/F: 1486/826

3. APACHE II, mean (SD): 23 (± 11)

Country: Belgium

Setting: 7 ICUs

Interventions

EN group (study authors referred to this group as "late‐initiation group")

n = 2328; 15 discontinued intervention owing to protocol violation (inadvertent administration of ≥ 1 L/day PN for ≥ 2 days during intervention period); 2328 analysed as ITT

Details: IV 20% glucose solution (target for total energy intake was 400 kcal/day on 1st ICU day, and 800 kcal/day on 2nd ICU day), and EN via duodenal feeding tube. If EN was insufficient after 7 days, PN was initiated on day 8 to reach caloric goal. Continuous insulin infusion adjusted to obtain blood glucose level 80 to 100 mg/dL

EN + PN group (study authors referred to this group as "early‐initiation group")

n = 2312; 0 losses; 2312 analysed

Details: IV 20% glucose solution (target for total energy intake was 400 kcal/day on first ICU day, and 800 kcal/day on second ICU day). On day 3, PN initiated with dose targeted to 100% of caloric goal through combined EN + PN (except when clinicians predicted that participant would tolerate sufficient EN or oral feeding on day 3). Amount of PN was calculated as amount that was not effectively delivered by EN. Calculations of caloric goal included protein energy and based on ideal bodyweight, age, and gender. PN was reduced and eventually stopped if participant was able to meet > 80% caloric goal with EN or able to resume normal oral feeding. Continuous insulin infusion adjusted to obtain blood glucose level 80 to 100 mg/dL

Outcomes

1. Death (number of participants alive at discharge from ICU in ≤ 8 days, death in the ICU and in hospital, survival up to 90 days)

2. Rates of complications, and hypoglycaemia

3. Number of ICU days and time to discharge from the ICU

4. Number of participants with new infections (airways, lungs, bloodstream, urinary tract, wounds)

5. Duration of antibiotic therapy

6. Inflammation

7. Time to weaning from mechanical ventilation and need for tracheostomy

8. Acute kidney injury (using RIFLE)

9. Renal replacement therapy

10. Need for and duration of pharmacological or mechanical haemodynamic support

11. Liver dysfunction

12. Duration of hospital stay

13. Functional status at discharge (6‐minute walk test and participants who were independent in ADL)

14. Healthcare costs

Notes

Funding/declarations of interest: supported by Methusalem programme of the Flemish government, Research Fund of the Catholic University of Leuven, Belgium; the Research Foundation Flanders, Belgium; and the Clinical Research Fund of the University Hospitals Leuven, Belgium. In addition, the Catholic University of Leuven received unrestricted research grant from Baxter Healthcare for less than one‐third of study costs. Baxter Healthcare were not involved in the design of study, collection, analysis, or interpretation of data, in preparation of manuscript for publication.

Study dates: August 2007 to November 2010

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of a digital system to prepare order of envelopes

Allocation concealment (selection bias)

Low risk

Use of sequentially numbered, sealed, opaque envelopes, and block size was concealed from treating physicians and nurses

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed that investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Low risk

All outcome assessors were blinded to group allocation

Blinding of outcome assessment (detection bias)
Mortality

Low risk

All outcome assessors were blinded to group allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Small number of losses in 1 group, unlikely to influence outcome data

Selective reporting (reporting bias)

Low risk

Prospective clinical trials registration (NCT00512122). Outcomes reported same as clinical trials registration documents. We noted that duration of ICU was reported but not listed in the registration documents, but primary outcomes were generally all reported

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

Protocol for glycaemic management was the same for both groups. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 70

Inclusion criteria

1. Adults, phase of persistent hypermetabolism 4 to 6 days after sepsis and surgery

Exclusion criteria

1. Known cirrhosis

2. Severe malnutrition

3. Known diabetes mellitus requiring insulin

4. Receiving steroids

5. Undergoing chemotherapy

Primary diagnosis

1. Persistent hypermetabolism after sepsis

Baseline characteristics

EN group

1. Age, mean (SD): 56 (± 15) years

2. Gender, M/F: 20/13

3. APACHE II: not reported

PN group

1. Age, mean (SD): 55 (± 11) years

2. Gender, M/F: 22/15

3. APACHE II: not reported

Country: USA

Setting: surgical ICU

Interventions

EN group

n = 33; 2 losses; ITT analysis = 31 analysed

Details: nasoduodenal feeding, started 4 to 6 days after sepsis and surgery, target rate of 1.5 g protein/kg/day. 30 NPC/kg/day, carbohydrates, protein, fats, salts, minerals etc. Duration of feeding assumed to be for 8 to10 days

Note: 10 participants given PN during period prior to randomization

Caloric intake received, mean (SD): protein: 80 (± 26) g/day. Non‐protein: 1684 (± 573) kcal/day

PN group

n = 37; 2 losses: ITT analysis = 35 analysed

Details: feeding formula described as "identical composition" to EN group, with same target rate of delivery

Note: 10 participants given PN during period prior to randomization

Caloric intake received, mean (SD): protein: 88 (± 20) g/day. Non‐protein: 2000 (± 20) kcal/day

Outcomes

1. Mortality (during ICU stay)

2. Multiple organ failure

3. Diarrhoea and vomiting

Notes

Funding/declarations of interest: no details reported

Study dates: not reported

Note: participants in study were a subgroup of a larger epidemiological study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss of 4 participants, with reasons reported by study authors; small number of losses unlikely to influence data

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not feasible to judge risk of reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

No details of glycaemic controls, limited detail in paper but nutritional composition is described as identical. We noted more calories in PN group, but study authors reported "no statistical difference."

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Number of randomized participants: 24

Inclusion criteria

1. People requiring artificial nutrition and able to use gastrointestinal tract for the purpose

Exclusion criteria

1. Not reported

Primary diagnosis

1. Multiple trauma

2. Guillain‐Barré syndrome

3. Intracerebral/subarachnoid bleed

4. Gastric carcinoma

5. Intestinal carcinoma

6. Hypoxic coma

Baseline characteristics

EN group

1. Age, mean (range): 52 (17 to 78) years

2. Gender: not reported

3. SAPS II, mean (SD): 10 (± 4)

EN + PN group

1. Age, mean (range): 49 (18 to 77) years

2. Gender: not reported

3. SAPS II, mean (SD): 11 (± 4)

Country: Italy

Setting: ICU

Interventions

EN group

n = 12: no apparent losses

Details: nutrition initiated 24 to 36 hours after admission. All participants fed with PN for 4 days, then 'weaned' to EN. Nasogastric tube placement, duration of feeding for 7 days, with formula consisting of high protein content with high ratio of calories/nitrogen.

Caloric intake received, mean (SD): 33 (± 9) kcal/kg

EN with PN group

n = 12; no apparent losses

Details: nutrition initiated 24 to 36 hours after admission. All participants given PN for 4 days, then given mixed feeding of 50% PN and 50% EN

Caloric intake received, mean (SD): 31 (± 6) kcal/kg

Outcomes

1. Metabolic indices

2. Incidence of diarrhoea (diagnosed by faecal mass of > 700 g/day)

3. Nitrogen balance

4. Infection (measured by blood cultures, chest x‐ray, and bronchoaspirates)

5. Duration of mechanical ventilation

6. LOS, mortality (time point not reported)

Notes

Funding/declarations of interest: not reported

Study dates: not reported

Study report published in Italian

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants randomly assigned to groups but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trial registration or publication of prospective protocol not reported; not feasible to judge risk of reporting bias

Baseline characteristics

Low risk

Study authors reported that baseline characteristics were comparable

Other bias

Unclear risk

No other sources of bias identified

Methods

RCT, single‐centre, 3‐arm, parallel design

Participants

Total number of randomized participants: 38

Inclusion criteria

1. Blunt traumatic event, GCS ≥ 5, ISS ≥ 15

2. No spinal neuropathy above 8th thoracic spinal level

3. No major fluid restriction requirement

4. Aged 18 to 60 years

5. Able to undergo upper gastrointestinal endoscopy

6. Respiratory insufficiency that mandated need for mechanical ventilation for ≥ 48 hours

Excluded criteria

1. If randomization did not take place within 30 hours after admission or admission did not occur within 12 hours after injury

Primary diagnoses

1. Blunt trauma injuries

Baseline characteristics

EN group

1. Age: not reported

2. Gender: not reported

3. APACHE II: not reported

4. GCS, mean (SD): 11 (± 5)

5. ISS, mean (SD): 34 (± 18)

PN group

1. Age: not reported

2. Gender: not reported

3. APACHE II: not reported

4. GCS, mean (SD): 12 (± 3)

5. ISS, mean (SD): 38 (± 12)

EN + PN group

1. Age: not reported

2. Gender: not reported

3. APACHE II: not reported

4. GCS, mean (SD): 11 (± 4)

5. ISS, mean (SD): 37 (± 15)

Country: USA

Setting: trauma centre

Interventions

EN group

n = 12; 0 losses

Details: transpyloric tube placement, feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aimed to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. Formula was Traumacal (Mead‐Johnson), NPC given in form of lipids (30%) and carbohydrates (70%). Ratio of NPC to nitrogen was 105:1. Protein load was 1.75 g/kg/day.

Mean caloric intake: 1789 calories/day for 7 days

PN group

n = 16; 1 participant died on 4th study day, not included in study analysis but we have included in review outcome data.

Details: feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aim to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. Formula consisted of dextrose‐lipid‐AA mixture; soybean solution, multi‐vitamin mixture. Mixture was 6.7% AA and 23.1% dextrose, soybean solution provided 30% of the NPC.

Mean caloric intake: 1961 calories/day for 7 days

EN + PN group

n = 10; 0 losses

Details: feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aim to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. EN formula provided 50% of calories and PN formula provided 50% of calories. EN consisted of Traumacal (Mead‐Johnson), NPC given in form of lipids (30%) and carbohydrates (70%). PN formula consisted of dextrose‐lipid‐AA mixture; soybean solution, multi‐vitamin mixture.

Mean caloric intake: 2030 calories/day for 7 days

Outcomes

1. Number of ventilator days

2. Number of ICU days

3. Total hospital stay

4. Presence of ARDS

5. Respiratory infection

6. Any infection

7. Renal failure

8. Icterus

9. Death

10. Hospital and professional charges

Notes

Funding/declarations of interest: not reported

Study dates: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Low risk

Most outcome data were taken from the trauma registry.

Quote: "All data from the trauma registry and the finance officers were blinded, since these sources had no knowledge of the patient's status relative to the research arm assigned."

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 participant was not included in data for PN group due to death during 7‐day intervention period; we have included this event in review analysis. No other loss of data

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration or prospectively published protocol not reported; not feasible to judge risk of selective outcome reporting bias

Baseline characteristics

Low risk

Some usual baseline characteristics not reported (age, gender) but other characteristics all appeared comparable

Other bias

Unclear risk

Target rate of nutrition the same. Unclear if differences in formula were equivalent

Methods

RCT, single‐centre, 3‐arm, parallel design

Participants

Number of randomized participants: 20

Inclusion criteria

1. APACHE II score > 10, requiring ≥ 7 days of nutritional support, 18 to 65 years of age

Exclusion criteria

1. Abdominal injury

2. Gastrointestinal stenosis

3. Liver or renal insufficiency

4. High catecholamine requirement

5. Acute or severe pancreatitis

6. Post‐transplantation surgery

7. Taking cortisone medication

8. Immunosuppressant therapy and autoimmune illnesses

Primary diagnoses

1. Multiple trauma

Baseline characteristics

EN group (standard)

1. Age, mean (SD): 41 (± 16) years

2. Gender, M/F: 10/0

3. APACHE II, mean (SD): 16.3 (± 4.5)

EN group (supplemented)

1. Age, mean (SD): 33 (± 13) years

2. Gender M/F: 8/2

3. APACHE II, mean (SD): 15.7 (± 4.4)

PN group

1. Mean age: 32 (SD ± 10) years

2. Gender M/F: 7/3

3. Mean APACHE II: 16.3 (SD ± 3.1)

Country: Germany

Setting: ICU

Interventions

EN group (standard)

n = 10; 0 losses

Details: nasojejunal tube with feeding pump, feeding started within 24 hours of trauma, "Oligopeptide standard diet" (Survimed OPD, Frensenius). Target energy of 25 kcal/kg/day. Initial rate of 25 mL/hour. Infusion rate increased at rate of 25 mL/hour up to the 4th day and a minimum of 75 mL/hour.

Caloric intake received: not reported

EN group (supplemented)

n = 10; 0 losses

Details: nasojejunal tube with feeding pump, feeding started within 24 hours of trauma. Formula consisted of Impact (Fa. Sandoz), supplemented with arginine, omega‐3 fatty acids, nucleotide, and selenium. Target energy of 25 kcal/kg/day. Initial rate of 25 mL/hour. Infusion rate increased at rate of 25 mL/hour up to the 4th day and a minimum of 75 mL/hour.

Caloric intake received: not reported

PN group

n = 10; 0 losses

Details: isocaloric and isonitrogenous total PN

Caloric intake received: not reported

Outcomes

1. Septic complications (diagnosed according to the ACCP/SCCM definitions)

2. Immunological measurements

Notes

Funding/declarations of interest: not reported

Study dates: not reported

Note: for the purpose of review analysis, we combined data for the 2 EN groups.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration of prospectively published protocol not reported; not feasible to assess risk of reporting bias

Baseline characteristics

Low risk

Appear comparable

Other bias

Low risk

No other sources of bias identified

Methods

RCT, single‐centre, 3‐arm, parallel design

Participants

Total number of randomized participants: 120

Inclusion criteria

1. Admitted to the NICU, with diagnosis of severe TBI, GCS score 6 to 8, NRS ≥ 3

Exclusion criteria

1. Glucocorticoid and blood products were used during the study

2. Haemodynamic instability

3. Immunosuppressive drug used in the past 6 months

4. Received radiotherapy or chemotherapy in the past year

5. Injured > 12 hours before admission

6. Died within 3 weeks

7. Previous history of metabolic diseases such as diabetes mellitus

Primary diagnosis

1. Severe TBI

Baseline characteristics

EN group

1. Age, mean (SD): 40.12 (± 11.25) years

2. Gender, M/F: 18/22

3. APACHE II: not reported

PN group

1. Age, mean (SD): 41.56 (± 15.10) years

2. Gender, M/F: 21/19

3. APACHE II: not reported

EN + PN group

1. Age, mean (SD): 42.31 (± 14.18) years

2. Gender, M/F: 23/17

3. APACHE II: not reported

Country: China

Setting: NICU

Interventions

EN group

n = 40; 0 losses

Details: all participants had nasogastric tube intubation and central venous catheterization within 48 hours of admission. EN given via nasogastric tube accompanied by suctioning gastric tube, within 48 hours of admission. Increasing dose to a maximum of 1500 mL/day in 7 days, with a pumping speed < 75 mL/hour. Normal sodium, glucose, and saline given IV. Energy as 105 to 126 kJ/kg/day. Supplements of vitamins, micro‐elements, natrium, and kalium given if required

PN group

n = 40; 0 losses

Details: all participants had nasogastric tube intubation and central venous catheterization within 48 hours of admission. Participants given PN through central venous catheter within 48 hours. Ratio of 2:1 for carbohydrates to lipids, and ratio of 100:1 for calorie nitrogen ratio. Energy as 105 to 126 kJ/kg/day. Supplements of vitamins, micro‐elements, natrium, and kalium given if required

EN + PN group

n = 40; 0 losses

Details: all participants had nasogastric tube intubation and central venous catheterization within 48 hours of admission. EN given via nasogastric tube accompanied by suctioning gastric tube, within 48 hours of admission. Increasing dose to a maximum of 1000 mL/day in 7 days, with a pumping speed < 50 mL/hour. Insufficient energy was given by PN. Energy as 105 to 126 kJ/kg/day. Supplements of vitamins, micro‐elements, natrium, and kalium given if required

Outcomes

1. Nutritional status measurements (serum total protein, serum albumin, serum prealbumin, haemoglobin)

2. Immune function (T cells subsets and immunoglobulin)

3. Complications (diarrhoea, stress ulcer, intracranial infection, pyaemia, hypoproteinaemia, aspirated pneumonia)

4. LOS in NICU

5. Mechanical ventilation status and duration

6. Death

Notes

Funding/declarations of interest: supported by the Natural Science Foundation of Shandong province, and Technology Supporting Program of Qingdao

Study dates: January 2009 to May 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quasi‐randomized method of sequence generation. Participants were randomly allocated according to hospital record numbers

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details. Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration of prospectively published protocol not reported; not feasible to assess risk of reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Number of randomized participants: 60

Inclusion criteria

1. Postoperative participants undergoing surgery for abdominal cancer

Exclusion criteria

1. Not reported

Primary diagnoses

1. Gastric, colon, and rectal cancer

Baseline characteristics

EN group

1. Age, mean (SD): 65.1 (± 12.2) years

2. Gender, M/F: 17/13

3. APACHE II: not reported

PN group

1. Age, mean (SD): 67.3 (± 11.6) years

2. Gender, M/F: 19/11

3. APACHE II: not reported

Country: Turkey

Setting: ICU

Interventions

EN group

n = 30; no apparent losses

Details: nasogastric or jejunum feeding, initiated within 12 hours of surgery with target rate of delivery at 35 kcal/kg/day

PN group

n = 30; no apparent losses

Details: standard formula of TPN (75% carbohydrate, 25% fat), with target rate of delivery at 35 kcal/kg/day

Outcomes

1. Immunology measurements

2. Postoperative complications (including wound, pulmonary, and urinary infections; intra‐abdominal abscess)

3. ICU and hospital stay

4. Mortality

Notes

Funding/declarations of interest: funding not reported. Study authors declared no conflicts of interest.

Study dates: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to groups; no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

We assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported; not feasible to assess risk of reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Unclear risk

No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 24

Inclusion criteria

1. > 3 days in ICU

Exclusion criteria

1. People in ICU for brief period (< 72 hours)

2. Serial measurement of gastrointestinal tract permeability could not be made

3. People with a history of malabsorption or who had undergone bowel surgery, people in renal failure

Primary diagnoses

1. Surgery for cardiopulmonary bypass

2. Respiratory failure

Baseline characteristics

Overall gender, M/F: 17/7

EN group

1. Age, mean (SEM): 66.2 (± 2.0) years

2. APACHE II, mean (SD): 16.9 (± 1.2)

PN group

1. Age, mean (SEM): 64.6 (± 2.6) years

2. APACHE II, mean (SD): 13.3 (± 1.2)

Country: UK

Setting: adult ICU

Interventions

EN group

n = 13; 0 losses

Details: nasogastric tube placement, formula used was Alitraq (Abbott Laboratories), supplemented with glutamine, delivered at 30 mL/hour (rate increased to meet nutritional requirements during 24 to 36 hours). Sucralfate (for stress ulcers) also given when required.

PN group

n = 11; 0 losses

Details: formula described as standard regimen (Kabi 1 or Kabi 2 ‐ Kabi Pharmacia, Ltd, Milton Keynes, UK). Did not include glutamine supplement. Sucralfate (for stress ulcers) also given when required.

Outcomes

1. Mortality

2. Gastrointestinal tract absorption and permeability

Notes

Funding/declarations of interest: Abbott Laboratories Ltd

Study dates: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not possible to make judgement on risk of bias for selective outcome reporting

Baseline characteristics

Low risk

Appeared comparable

Other bias

Unclear risk

Glutamine supplement given to EN group but not PN group

Methods

RCT, multi‐centre, 2‐arm, parallel design

Participants

Total number of participants: 2400

Inclusion criteria

1. ≥ 18 years of age

2. Expected to require nutritional support for ≥ 2 days, within 36 hours of admission to ICU that was expected to last ≥ 3 days

Exclusion criteria

1. Participants could not be fed through either PN or EN route

2. Received nutritional support in previous 7 days

3. Had a gastrostomy or jejunostomy in situ

4. Were pregnant

5. Not expected to be in the UK for next 6 months

Primary diagnoses

1. Study authors reported co‐existing illnesses as liver, renal, respiratory, cardiovascular, and immunodeficiency

Baseline characteristics

EN group

1. Age, mean (SD): 62.9 (± 15.4) years

2. Gender, M/F: 725/472

3. APACHE II, mean (SD): 19.6 (± 7.0)

4. SOFA, mean (SD): 9.6 (± 3.3)

PN group

1. Age, mean (SD): 63.3 (± 15.1) years

2. Gender, M/F: 689/502

3. APACHE II, mean (SD): 19.6 (± 6.9)

4. SOFA, mean (SD): 9.5 (± 3.4)

Country: UK

Setting: 33 ICUs

Interventions

EN group

n = 1200; 1195 analysed; participants lost to follow‐up were not included in analysis, but protocol deviations were. See note

Details: nasogastric or nasojejunal tube feeding for 5 days. Time of initiation of feeding: median 22 (IQR 16 to 28) hours. Target rate of 25 kcal/kg bodyweight/day, with goal to reach target within 48 to 72 hours. Prokinetics given for GRV cut‐offs at 200 to 500 mL. Use of international guidelines for glycaemic management, plus target level for serum glucose of < 180 mg/dL (10 mmol/L)

Caloric intake received, mean (SD): 74 (± 44) kcal/kg

PN group

n = 1200; 1188 analysed; participants lost to follow‐up were not included in analysis, but protocol deviations were

Details: central venous catheter placement. Target rate of delivery as for EN. Equivalent nutritional formula as EN, with same glycaemic management. IV feeding for 5 days, then weaned to gastric feeding. Time of initiation of feeding of feeding: median 24 (IQR 17 to 30) hours

Caloric intake received, mean (SD): 89 (SD ± 44) kcal/kg

Outcomes

1. All‐cause mortality at 30 days, discharge, 90 days, and 1 year

2. Length of ICU and hospital stay

3. Infectious and non‐infectious complications (including hyperglycaemia, defined as any new episode of hyperglycaemia during study period)

4. Duration of organ support

Notes

Funding/declarations of interest: NIHR

Study dates: June 2011 to March 2014

Protocol deviations: EN: 30 did not receive assigned nutritional support, 26 received no nutritional support, 4 received PN. PN: 36 did not receive assigned nutritional support, 24 received no nutritional support, 12 received EN. All analysed as ITT. Additionally, there was a cross‐over of 18 participants in the EN group and 81 participants in the PN group, but these occurred towards the end of feeding and did not constitute protocol deviations.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate sequence generation. 24‐hour telephone randomization system with computer algorithm used to balance groups in ICU

Allocation concealment (selection bias)

Low risk

Telephone randomization system and we assumed that allocation was concealed from investigators

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Small number lost to follow‐up and not included in ITT analysis. Some protocol deviations but less than 10%; ITT analysis used for these

Selective reporting (reporting bias)

Low risk

Prospective clinical trials registration ISRCTN17386141. Protocol outcomes were consistent with outcomes reported in published study

Baseline characteristics

Low risk

Appear comparable

Other bias

Unclear risk

Not enough information on nutritional formula to make judgement. "Standard stock supply" used. Glycaemic controls appeared the same

Methods

RCT, multi‐centre, 2‐arm, parallel design

Participants

Total number of participants: 305

Inclusion criteria

1. People who received < 60% of their energy target from EN at day 3 after admission to the ICU

2. Expected to stay for > 5 days

3. Expected to survive for > 7 days

4. Had a functional gastrointestinal tract.

Exclusion criteria

1. People who were receiving PN

2. Had persistent gastrointestinal dysfunction and ileus

3. Were pregnant

4. Refused to consent

5. Had been readmitted to the ICU after previous randomization

Primary diagnoses

1. Shock

2. Neurological

3. Cardiac surgery

4. Polytrauma

5. Pneumonia

6. Cardiac arrest

7. Respiratory failure

8. Myocardial infarction

9. Acute pancreatitis

10. Liver failure

11. Other

Baseline characteristics

EN group

1. Age, mean (SD): 60 (± 16) years

2. Gender, M/F: 105/47

3. APACHE II, mean (SD): 23 (± 7)

4. SAPS II, mean (SD): 47 (± 15)

EN + PN group

1. Age, mean (SD): 61 (± 16) years

2. Gender, M/F: 110/43

3. APACHE II, mean (SD): 22 (± 7)

4. SAPS II, mean (SD): 49 (± 17)

Country: Switzerland

Setting: 2 ICUs, medical and surgical

Interventions

EN group

n = 152; 10 participants discontinued study due to protocol violations; ITT analysis

Details: nasogastric tube feeding (preferable). All participants fed EN until day 3. Participants in EN group continued with EN feeding for 5 days as part of intervention period, then remained on EN for 28 days as required. Target rate of delivery for women 25 kcal/kg of ideal bodyweight/day, for men 30 kcal/kg of ideal bodyweight/day. Protein delivery at 1.2 g/kg of ideal bodyweight/day, formula consisted of polymeric, fibre‐enriched formulas, routinely prescribed in both hospitals, containing 1.05 to 1.62 kcal/mL of energy (18% proteins, 29% lipids (8% medium‐chain triglycerides), 53% carbohydrates). Prokinetics given if GRV ≥ 300 mL. Continuous IV insulin therapy to maintain blood glucose at lower than 8.5 mmol/L.

Caloric intake received, mean (SD): 20 (± 7) kcal/kg/day for days 4 to 8

EN + PN group

n = 153; 20 participants discontinued study due to protocol violations; ITT analysis

Details: central or peripheral catheter placement. All participants fed with EN formula until day 3. Participants in EN + PN group supplemented with PN feeding for 5 days, then resumed with only EN for 28 days as required. Target rate of delivery as for EN. EN formula as above. Formula for PN consisted of 0.62‐1.37 kcal/mL of energy (20% proteins, 29% lipids (15% medium‐chain triglycerides), and 51% carbohydrates).

Caloric intake received, mean (SD): 28 (± 5) kcal/kg/day for days 4 to 8

Outcomes

1. Nosocomial infections after day 8 until day 28

2. LOS in the ICU and hospital until day 28

3. Mortality in the ICU

4. General mortality

5. Duration of invasive mechanical ventilation

Notes

Funding/declarations of interest: Foundation Nutrition 2000Plus, ICU Quality Funds, Baxter, and Fresenius Kabi. Study authors reported that, "sponsors of study had no role in study design, data collection, data analysis, data interpretation, or writing of the report."

Study dates: December 2008 to December 2010

Note: study authors reported number of infections, rather than number of participants with an infection, and we could not report this data because we did not know if a participant had more than 1 infection

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate sequence generation. Computer‐generated randomization sequence

Allocation concealment (selection bias)

Low risk

Adequate allocation concealment. Sequentially numbered, sealed, opaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Some attempts to reduce risk of bias; study investigators involved in decisions regarding caloric goal were blinded. However, other investigators, personnel, and participants were not blinded

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Low risk

Quote: "The senior site investigator from each university hospital prospectively obtained information about infectious episodes in study patients from the other centre, and was unaware of the treatment groups assigned to patients."

Attempts to reduce outcome assessor and statistician blinding sufficient for our review outcomes

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Assume blinding of outcome assessors for blinding; and lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

20 participants in EN + PN group, and 10 participants in EN group discontinued study mostly due to protocol violation. Study authors used an ITT analysis. We noted an uneven number of losses between groups, with > 10% loss in the EN + PN group, and that death before 9 days was classed as protocol violation. We assumed that participants who died were included in mortality data for this study

Selective reporting (reporting bias)

Unclear risk

Quote: "registered with ClinicalTrials.gov, number NCT00802503"

Prospective registration. All outcomes reported in trial register documents were consistent with reported outcomes. However, we noted changes to the trial registration documents after completion of the trial to state time point for data collection of infections between day 9 to day 28. We could not be certain whether this change affected the data reported in the published study

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

No other sources of bias identified. No evidence of differences in glycaemic controls or nutritional protocol

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 22

Inclusion criteria

1. 18 to 60 years of age, admitted to the ICU, diagnosed with TBI (GCS 9 to 12)

Exclusion criteria

1. Chronic renal failure

2. History of COPD

3. Hepatic dysfunction or cirrhosis or bilirubin > 3 mg%

4. Insulin‐dependent diabetes mellitis

5. Morbid obesity

6. Pre‐existing malnutrition

7. Pregnancy

8. Immune depressive conditions

9. Associated abdominal trauma

10. Participants excluded if not able to receive treatment for 2 consecutive days

Primary diagnoses

1. TBI

Baseline characteristics

EN group

1. Age, mean (SD): 31 (± 13) years

2. Gender, M/F: 11/1

3. APACHE II, mean (range): 14 (8 to 22)

PN group

1. Age, mean (SD): 31 (± 10) years

2. Gender, M/F: 9/1

3. APACHE II, mean (range): 13 (7 to 21)

Country: Brazil

Setting: ICU

Interventions

EN group

n = 12: 0 losses

Details: oro‐ or naso‐feeding tube in gastric position with pump infusion. Feeding initiated as soon as participant was haemodynamically stable. Duration of feeding for 5 days, with target rate of delivery of 25 to 30 kcal/kg/day with 1.5 g/kg/day of protein. Composition of feeding solution per 100 mL: protein 3.6 g (70% soy protein), carbohydrate 14 g, lipids 3.5 g added with casein to reach 1.5 g/kg/day

Caloric intake received, mean (SD): total during 5 days: 5958 (± 3619) kcal

PN group

n = 10; 0 losses

Details: central venous access, with equivalent target rate of delivery as EN group. Composition of feeding solution per 100 mL: 3.8 g of AAs, 14 g of glucose and 3.3 g or lipids

Caloric intake received, mean (SD): total during 5 days: 6586 (± 1052) kcal

Outcomes

1. Mortality

2. Morbidity

3. Length of ICU stay

4. Days of mechanical ventilation

5. Pneumonia

6. Sepsis

Notes

Funding/declarations of interest: not reported

Study dates: August 2008 to June 2009

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence assessment of mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Details of clinical trial registration not reported. Not possible to make assessment of selective outcome reporting bias

Baseline characteristics

Low risk

All comparable

Other bias

Low risk

Glycaemic controls not reported. We noted no differences in nutritional protocol. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 98

Inclusion criteria

1. 18 years of age, intra‐abdominal injury requiring laparotomy, with ATI ≥ 15

Exclusion criteria

1. Not reported

Primary diagnoses

1. Abdominal trauma

Baseline characteristics

EN group

1. Age, mean (SEM): 30.4 (± 1.7) years

2. Gender, M/F: not reported

3. APACHE II: not reported

PN group

1. Age, mean (SEM): 30.6 (± 1.4) years

2. Gender, M/F: not reported

3. APACHE II: not reported

Country: USA

Setting: trauma ICU

Interventions

EN group

n = 52; 1 death within 4 days, excluded from study analysis but we included in the review analysis; 2 participants were switched to PN group at 1 week, included in ITT analysis

Details: feeding tube placement in jejunum. Target rate of delivery 1.5 to 2.0 g/kg/day of protein/AAs and 30 to 35 kcal/kg/day of NPC. Participants randomized within 8 hours of surgery, mean (SD) time until initiation of feeding was 24 (± 1.7) hours. Feeding formula was Vital HN (Ross Laboratories, Columbus, OH, USA), and consisted of protein (16.7%), branched‐chain AAs (18.2%), carbohydrates (73.9%), and fat (9.4%)

Caloric intake received, mean (SEM): 30.2 (± 1.2) NPC/kg/day (maximum rate). Participants in the EN group received significantly less total nutrition per day than participants in the PN group.

PN group

n = 46; 1 death within 4 days, excluded from study analysis but we included in the review analysis; of 40 participants, people with infections were transferred to EN group, but kept in analysis as ITT

Details: central venous access. Target rate of delivery as for EN group. Mean (SD) time until initiation of feeding was 22.9 (± 1.6) hours. Pharmacy provided formula with similar concentrations of protein, carbohydrate, and fat.

Caloric intake received, mean (SEM): 29.9 (± 15) NPC/kg/day

Outcomes

1. Length of hospital stay

2. Number of ventilator days

3. Septic morbidity (to include pneumonia (diagnosed by symptoms of fever, leukocytosis, positive sputum/bronchoalveolar lavage specimens, purulent sputum, development of new pulmonary infiltrates)

4. Intra‐abdominal abscess

5. Emphysema

6. Line sepsis (diagnosed by symptoms of purulence of exit site of catheter, positive catheter cultures in association with positive blood cultures)

Notes

Funding/declarations of interest: not reported

Study dates: December 1989 to August 1991

Note: 8 participants (did not state from which groups) required return to surgery within 24 to 48 hours, then randomized to receive EN or PN. Assumed that analysis and baseline characteristics were from point of new randomization (i.e. participants were removed and then re‐introduced into the study. 2 participants were switched from EN to PN because of failure to tolerate ≥ 50% or nutritional goal; use of ITT analysis for these participants. Protocol broken for 6 participants who had candida infections (4 in PN group, 2 in EN group)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization table

Allocation concealment (selection bias)

Low risk

Computer randomization and we assumed that allocation was concealed from investigators

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel.

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

Principal investigator, who we assumed was not blinded, was involved in data analysis (review of charts at hospital discharge). However, attempts were made to reduce bias by using a 2nd blinded surgeon to resolve discrepancies in infections diagnoses

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 participants excluded from analysis due to death; included in review analysis

Selective reporting (reporting bias)

Unclear risk

No protocol or clinical trials registration reported, therefore, not feasible to make judgement on risk of selective reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Unclear risk

Some changes to feeding protocols that were deemed clinically appropriate. Use of ITT analysis

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 59

Inclusion criteria

1. Adults undergoing emergency celiotomy, ATI > 15 and < 40

Exclusion criteria

1. Pelvic fractures that required > 6 units of blood in first 12 hours of hospital admission

2. Total blood loss > 25 units in the first 24 hours

3. Repeat laparotomy within 72 hours

4. Treatment with steroids or chemotherapy

Primary diagnosis

1. Abdominal trauma

Baseline characteristics

EN group

1. Age, mean (SEM): 28.3 (± 1.9) years

2. Gender, M/F: 17/4

PN group

1. Age, mean (SEM): 31.4 (± 2.4) years

2. Gender M/F: 20/5

Country: USA

Setting: ICU

Interventions

EN group

n = 29; 8 losses, participants withdrawn due to: failure to meet inclusion/exclusion criteria, presence of underlying bowel disease, mechanical failure of EN delivery, early patient transfer, death within 72 hours; 21 analysed

Details: needle‐catheter jejunostomy placed at initial laparotomy. BEE calculated by Harris‐Benedict equation at 1.5 x BEE. Feeding initiated within 12 hours of surgery. Formula consisted of Vivonex TEN (Norwich Eaton Pharmaceuticals, Inc, Norwich, NY, USA); provided 2.5% fat and approximately 33% branched chain AAs with NPC to grams nitrogen ratio of 150:1

Caloric intake received, mean (SEM): day 5: 2203.7 (± 172.8) kcal/kg

PN group

n = 30; 5 losses, participants withdrawn due to: failure to meet inclusion/exclusion criteria, presence of underlying bowel disease, early patient transfer, death within 72 hours; 25 analysed

Details: central venous catheter placed at initial laparotomy. BEE calculated by Harris‐Benedict equation at 1.5 x BEE. Feeding initiated within 12 hours of surgery, except 2 participants for which feeding was initiated within 24 to 36 hours after laparotomy. Formula consisted of a mixture of FraAmine HBC 6.9% (Kendall‐McGaw Laboratories, Irvine, CA, USA) and TrophAmine 6% (Kendall‐McGaw Laboratories, Irvine, CA, USA); provided 2.5% fat and approximately 33% branched chain AAs with NPC to grams nitrogen ratio of 150:1

Caloric intake received, mean (SEM): day 5: 2548.1 (± 85.3) kcal/kg

Outcomes

1. Serum and protein levels

2. LOS in ICU

3. LOS in hospital

4. Septic complications

5. Adverse events (abdominal distension, cramping, increased residual volumes; intolerance to feedings secondary to prolonged ileus secondary to mesenteric trauma)

Notes

Funding/declarations: not reported

Study dates: February 1985 to September 1987

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomized by computer assignment"

Allocation concealment (selection bias)

Low risk

Computer randomization and we assumed that allocation was concealed from investigators.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Large number of losses after randomization. Explanations given, but it was unclear if the number of losses was balanced between groups

Selective reporting (reporting bias)

Unclear risk

Details of clinical trial registration not reported. Not possible to make assessment of selective outcome reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

No other sources of bias identified

Methods

RCT, multi‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 290

Inclusion criteria

1. > 18 years of age

2. Judged by attending physicians to need artificial ventilation and nutrition for ≥ 4 days

Exclusion criteria

1. Contraindication to PN or EN

2. Motor GCS < 4

3. Pure cerebral disease

4. Spinal trauma

5. Referral from ICUs in which participants had spent > 24 hours

Primary diagnoses

1. Respiratory failure

2. Cardiovascular failure

3. Neurological failure

4. Multiple organ failure

Baseline characteristics

EN group

1. Age, mean (SD): 51.5 (± 22.9) years; number of participants aged > 60 years were 68/142

2. Gender, M/F: 101/41

3. SAPS II, median (IQR): 35.5 (27 to 45)

4. SOFA, median (IQR): 6 (4 to 6)

PN group

1. Age, mean (SD): 49.2 (± 26.0) years; number of participants aged > 60 years were 63/145

2. Gender, M/F: 112/33

3. SAPS II, median (IQR): 37 (26 to 45)

4. SOFA, median (IQR): 6 (4 to 8)

Country: Italy

Setting: 33 adult ICUs

Interventions

EN group

n = 143; 1 participant met criteria for sepsis and not analysed (baseline characteristics excluded this participant), ITT was used for remaining participants. 142 participants analysed

Details: no details of feeding tube placement. Duration of feeding assumed to be 6 days, with mean (SD) time to initiation of feeding 30.1 (± 13.8) hours, started at 10 kcal/kg/day, rising to 25 to 28 kcal/kg/day by the 4th day. Nutritional formula consisted of 55% carbohydrates, 25% fat, 21% protein, 1.3 kcal/mL, containing per 100 mL: L‐arginine 0.8 g, omega‐3 fatty acids, omega‐6 fatty acids 0.7 g, vitamin E 2.9 mg, β‐carotene 0.75 mg, zinc 2.2 mg, and selenium 7 μg. Blood glucose kept < 180 mg/dL

Caloric intake received, mean (SD): 20.0 (± 8.3) kcal/kg/day

PN group

n = 147; 2 participants met criteria for sepsis and not analysed (baseline characteristics excluded this participant), ITT was used for remaining participants. 145 participants analysed

Details: mean (SD) time to initiation of feeding 32.0 (± 12.2) hours. Nutrition supplied by pump 24 hours/day, with target of 25 to 28 kcal/kg bodyweight/day. PN not supplemented with EN before day 6. Nutritional formula consisted of 59% carbohydrate, 23% fat, 18% protein, 1.2 kcal/mL

Caloric intake received, mean (SD): 23.7 (± 8.6) kcal/kg

Authors conducted an adjusted analysis for caloric differences and baseline differences; concluded that differences were not significant

Outcomes

1. 28‐day mortality (non‐severe septic and severe septic)

2. Sepsis or septic shock (septic shock participants only)

3. LOS

4. Organ failure

5. Ventilator days (non‐severe septic shock participants only)

Notes

Funding/declarations of interest: partially funded by Abbott Italia. Also unrestricted educational grant from AstraZeneca Italy

Study dates: November 1999 to December 2001

Participants stratified to severely septic and non‐severely septic. Early stopping of recruitment, initially of severely septic participants who had increased mortality in EN group, then of non‐severely septic due to low accrual rate

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate sequence generation, computer‐generated randomization

Allocation concealment (selection bias)

Low risk

Adequate allocation concealment, randomization code generated externally and communicated via telephone to ICUs

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

.

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 participants excluded from analysis and included in the analysis of associated study (Bertolini 2003) due to misdiagnosis. Not included in review analysis

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not feasible to assess risk of reporting bias

Baseline characteristics

Unclear risk

Some baseline characteristics imbalance.

Quote: "The PN group had more men than the iEN group, more patients coming from wards and fewer from emergency rooms, and more with multiple organ failure. Other baseline characteristics were similar in the two arms."

According to the adjusted analysis, these baseline differences did not confound the results

Other bias

Unclear risk

Blood glucose protocols equivalent between groups. Overall nutritional protocols were not comparable for the first 4 days of the study; an adjusted analysis was planned for this. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 38

Inclusion criteria

1. People with head injury: penetrating missile wounds or blunt head trauma causing intracranial haematomas

2. A major focal neurological deficit or unconsciousness, or both

Exclusion criteria

1. Severe extracranial injuries that were expected to alter metabolic demands or to delay use of standard EN, such as abdominal‐organ injury

Primary diagnosis

1. Head injury

Baseline characteristics

EN group

1. Age, mean (SD): 34.9 (± 3.76) years

2. Gender: not reported

3. APACHE II: not reported

PN group

1. Age, mean (SD): 29.2 (± 4.12) years

2. Gender: not reported

3. APACHE II: not reported

Country: USA

Setting: neurosurgical unit

Interventions

EN group

n = 18; 0 losses

Details: nasogastric tube placement. Feeding started as soon as possible after randomization, when bowel sounds were present and GRV <100 mL/hour. Study authors did not report target rate of delivery. Formula was Vital (Ross Laboratories, Columbus, Ohio, USA) ‐ 42 g protein, 10.8 g fat, 185 g carbohydrates per litre

Caloric intake received, mean: 685 calories and 4.0 g nitrogen per day

PN group

n = 20; 0 losses

Details: percutaneous intraclavicular subclavian vein catheter placement. Feeding started within 48 hours of admission. Study authors did not report target rate of delivery. Formula consisted of synthetic AAs 42.5 g/L, 25% dextrose, electrolytes, vitamins, trace elements. 10% soybean oil emulsion 250 to 500 mL/day. Insulin used to control hyperglycaemia as required

Caloric intake received, mean: 1750 calories and 10.2 nitrogen per day

Outcomes

1. Fluid intake and output

2. Use of respirator

3. Nosocomial infections (not reported)

4. Sepsis (not clearly reported)

5. Use of antibiotics

6. Serum glucose levels

7. Daily temperature peak

8. Use of dexamethasone

9. Participant mortality

10. Length of ICU stay

11. Length of Hospital stay

Notes

Funding/declarations of interest: supported, in part, by a grant from Baxter‐Travenol Laboratories

Study dates: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No evidence of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No evidence of blinding

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration not reported. Not feasible to assess risk of reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Low risk

Insulin use to control hyperglycaemia was described for the PN group and we assumed that this was the same for each group. No other sources of bias identified

Methods

RCT, multi‐centre, 2‐arm, parallel design. Pilot study

Participants

Total number of randomized participants: 125

Inclusion criteria

1. Critically ill adults > 18 years of age

2. Mechanically ventilated

3. Had acute respiratory failure

4. Were receiving EN or were to be initiated on EN within 48 hours of ICU admission

5. BMI < 25 kg/m² or > 35 kg/m², based on pre‐ICU actual or estimated dry weight

Exclusion criteria:

1. > 72 hours from ICU admission to consent, not expected to survive an additional 48 hours from screening evaluation

2. Lack of commitment to full aggressive care

3. Contraindication to EN deemed to require PN for the first 7 days of ICU admission

4. Already at goal rate of EN from screening evaluation

5. Already receiving PN on admission to ICU

6. Admitted diabetic ketoacidosis or non‐ketotic hyperosmolar coma

7. Pregnant or lactating

8. Clinical fulminant hepatic failure

9. Dedicated port of central line not available

10. Known allergy to study nutrients

11. Enrolment in another study

Primary diagnosis

1. Acute respiratory failure

2. Sepsis

3. Gastrointestinal

4. Neurological

5. Other (not described by study authors)

6. Trauma

7. Metabolic

8. Cardiovascular/vascular

9. Haematological

Baseline characteristics

EN group

1. Age, mean (SD): 55.1 (± 16.2) years

2. Gender, M/F: 39/34

3. APACHE II, mean (SD): 20.8 (± 7.2)

4. SOFA, mean (SD): 5.9 (± 3.6)

5. BMI, mean (SD): 33.2 (± 15.0) kg/m²

6. BMI < 25 kg/m²: 38 participants

7. BMI > 35 kg/m²: 35 participants

EN + PN group

1. Age, mean (SD): 55.8 (± 19.8) years

2. Gender, M/F: 21/31

3. APACHE II, mean (SD): 20.5 (± 6.4)

4. SOFA, mean (SD): 6.2 (± 3.5)

5. BMI, mean (SD): 33.5 (± 14.9) kg/m²

6. BMI < 25 kg/m²: 27 participants

7. BMI > 35 kg/m²: 25 participants

Country: Canada, USA, Belgium, France

Setting: 11 ICUs

Interventions

EN group

n = 73; 0 losses (for clinical outcomes)

Details: EN initiated at 20 mL/hour and increased by 20 mL/hour every 4 hours, until goal was reached. A standard polymeric solution with 1.2 (± 0.2) kcal/mL was used to standardize nutrition delivery. Continued for 7 days or until death

EN + PN group

n = 52; 0 losses (for clinical outcomes)

Details: PN given via central IV access. PN solution had similar caloric density to EN solutions (1.2 kcal/mL providing 0.06 to 0.09 g protein/mL). PN initiated at 20 mL/hour and increased by 20 mL/hour every 4 hours, until goal was reached. Continued for 7 days or until death

Outcomes

1. Amount of calories and protein received

2. Study feasibility assessment

3. ICU, hospital and 6‐month mortality

4. Development of infections

5. Duration of ICU stay

6. Multiple organ dysfunction

7. Duration of mechanical ventilation

8. Vital status and quality of life (Barthel Index, SF‐36)

9. Duration of hospital stay

10. Muscle function (ultrasounds, CT scans, hand‐grip strength, 6‐minute walk test)

Notes

Funding/declarations of interest: The National Institutes of Health; The Royal Alexandra Hospital Foundation, Edmonton, Canada; PN solutions and funding for assistance with distribution from Baxter Inc

Study dates: June 2011 to January 2015

Note: study specifically recruited participants who were underweight or overweight; BMI status was balanced between groups

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralized web‐based randomization system used to randomize participants to groups

Allocation concealment (selection bias)

Low risk

Centralized randomization system used, which would conceal allocation codes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No evidence of blinding

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses for clinical outcome data

Selective reporting (reporting bias)

Low risk

Prospective clinical trials registration (NCT01206166). Outcomes were reported according to clinical trials documents

Baseline characteristics

Low risk

Largely comparable

Other bias

Low risk

We identified no other sources of bias.

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 45

Inclusion criteria

1. 18 to 60 years of age

2. Fasting time > 14 days

3. ASA 1 to 3, condition allowed for EN

Exclusion criteria

1. Chronic renal failure

2. History of COPD

3. Hepatic dysfunction or cirrhosis or a bilirubin value > 3 mg/dL

4. Metabolic diseases

5. Severe anaemia

6. Blood coagulation dysfunction

7. Pregnancy or lactation

8. History of psychiatric illness

9. Underwent immunosuppressive therapy

Primary diagnoses

1. Severe acute pancreatitis

2. Duodenal distula

3. Pancreatic trauma

4. High intestinal obstruction

5. Biliary tract fistula

6. Inflammatory intestinal obstruction

Baseline characteristics

EN group

1. Age, mean (SD): 52.81 (± 11.68) years

2. Gender, M/F: 16/6

3. APACHE II, mean (SD): 7.56 (± 1.60)

PN group

1. Age, mean (SD): 50.07 (± 13.56) years

2. Gender, M/F: 17/6

3. APACHE II, mean (SD): 6.47 (± 1.39)

Country: China

Setting: ICU

Interventions

EN group

n = 22; 0 losses

Details: oro‐ or naso‐enteral feeding tube, in gastric position with pump infusion. All participants fed PN until randomization. EN nutrition commenced when condition of participant allowed EN feeding. Duration of feeding assumed to be 7 days. Target rate of delivery at 20 to 25 kcal/kg/day with protein 1.5 g/kg/day. Glucose adjusted to 10 mmol/L. If EN could not meet participant's caloric needs, then PN was used as supplement from 4th day.

PN group

n = 23; 0 losses

Details: central venous access. All participants fed PN until randomization and then participants in PN continued with feed. Duration of feeding unclearly reported but assumed to be 7 days. Target rate of delivery as for EN group.

Study authors reported no significant difference in the administered total calories between groups (P > 0.05)

Outcomes

1. LOS in ICU

2. Days on mechanical ventilation

3. SIRS score

4. Complications (to include cardiac, leakage of anastomosis, sepsis, respiratory, brain, renal, liver cholestasis, bleeding, thromboembolism)

5. Hospital costs

6. Mortality at day 28

7. Specific organ failure after 7 days

8. Inflammatory markers and immunological measurements

Notes

Funding/declarations of interest: not reported

Study dates: February 2010 to February 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no further detail

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed that investigators made no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

No details; lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No apparent losses

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration or prospectively prepared protocol not reported; not feasible to assess this domain

Baseline characteristics

Low risk

Appear comparable

Other bias

Low risk

Limited information concerning nutritional protocol or glycaemic controls. No other sources of bias identified

Methods

RCT, single‐centre, 2‐arm, parallel design

Participants

Total number of randomized participants: 51

Inclusion criteria

1. People with severe head injury: primary site of injury was the brain

Exclusion criteria

1. Brain‐dead within 4 days of entering the study, or whose families decided to withdraw consent within 5 days

Primary diagnosis

1. Severe head injury

Baseline characteristics

EN group

1. Age, mean (SD): 34.0 (± 2.92) years

2. Gender, M/F: 22/6

3. APACHE II: not reported

PN group

1. Age, mean (SD): 30.3 (± 2.67) years

2. Gender M/F: 20/3

3. APACHE II: not reported

Country: USA

Setting: medical centre

Interventions

EN group

n = 28; some early participant loss but study authors do not report to which group these participants belonged. 11 participants did not tolerate tube feedings and were switched to PN group; used ITT analysis

Details: nasogastric tube feeding, started as soon as feeding tube in place. Feeding assumed to be for duration of study (i.e. 18 days). Target rate of delivery set at 1.75 x Harris Benedict BEE and 1.5 g protein/kg bodyweight/day. Formula consisted of Traumacal (1.5 calories/mL and 22% protein, 40% fat, and 38% carbohydrate) or Ensure Plus (1.5 calories/mL and 14.7% protein, 32% fat, and 53.3% carbohydrate). Participants given metoclopramide 10 mg/6 hours to stimulate gastrointestinal motility. No participant was treated with corticosteroids

Cumulative intake of protein, mean (SEM): 1.35 (± 0.12) g/kg/day

PN group

n = 23; some early participant loss but study authors did not report to which group these participants belonged; use of ITT analysis

Details: feeding commenced within 48 hours of randomization. Feeding assumed to be for duration of study (18 days); however, participants were given EN once bowel sounds were present and GRV < 100 mL every 2 hours. Target rate of delivery set at 1.75 x Harris Benedict BEE and 1.5 g protein/kg bodyweight/day. Formula consisted of sterile AA/dextrose solutions, multi‐vitamins, trace elements, and IV lipids. 17% calories as protein, 41% as fat, 42% dextrose. No participant was treated with corticosteroids

Cumulative intake of protein, mean (SEM): 0.91 (± 0.09) g/kg/day

Outcomes

1. Caloric intake and nitrogen balance

2. Serum protein levels

3. Anthropometry

4. Immunity profile

5. Complications (infection, pneumonia (diagnosed by symptoms of elevated WBC count, increased premature cells, elevated temperature, positive sputum culture, visual evidence of infiltrate)

6. Aspiration pneumonia

7. Aspiration pneumonitis

8. Urinary tract infection

9. Septicaemia (diagnosed by symptoms of fever, positive blood cultures, increased WBC count, no hypotension)

10. Septic shock (diagnosed by additional symptoms of increased cardiac output, decreased systemic vascular resistance)

11. Diarrhoea

12. Mortality

Notes

Funding/declarations of interest: not reported

Study dates: not reported

Note: we assumed that study participants were in the ICU, although study authors did not report this in the paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomized but no additional details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No details and we assumed that there were no attempts to blind personnel

Blinding of outcome assessment (detection bias)
All outcomes (except mortality)

Unclear risk

No details

Blinding of outcome assessment (detection bias)
Mortality

Low risk

Lack of blinding unlikely to influence outcome data for mortality

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 participants were entered into the study but due to exclusion criteria were excluded from analysis, included 5 deaths within 4 days. Study authors did not report to which group these participants belonged

Selective reporting (reporting bias)

Unclear risk

Clinical trials registration or prospectively prepared protocol not reported; not feasible to assess risk of reporting bias

Baseline characteristics

Low risk

Appeared comparable

Other bias

Unclear risk

Participants in PN group received more calories until the 9th day of study, and 11 EN participants required PN